Experimental co-transmission of Simian Immunodeficiency Virus (SIV) and the macaque homologs of the Kaposi Sarcoma- Associated Herpesvirus (KSHV) and Epstein- Barr Virus (EBV)
Experimental co-transmission of Simian Immunodeficiency Virus (SIV) and the macaque homologs of the Kaposi Sarcoma- Associated Herpesvirus (KSHV) and Epstein- Barr Virus (EBV)
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DOI：
10.1371/journal.pone.0205632
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发表时间：
2018-11-16
期刊：
影响因子：
3.7
通讯作者：
Rose, Timothy M.
中科院分区：
文献类型：
--
作者：
Bruce, A. Gregory;Barcy, Serge;Rose, Timothy M.
猕猴RFHV和LCV分别是人KSHV和EBV的同源物。由于缺乏可培养的感染性病毒来源，尚未开发RFHV的实验模型。在华盛顿国家灵长类动物研究中心对猕猴进行的筛查中，在先前疫苗研究中SIV感染猕猴的唾液中检测到RFHV。通过接种来自SIV感染的猪尾猕猴和食蟹猴供体的唾液来启动两只幼稚幼年猪尾猕猴的中试实验感染，所述唾液含有高水平的相应物种特异性RFHV菌株的DNA（> 10（6）基因组/ml）。两个青少年受者发生SIV和RFHV感染，感染后16周左右在唾液和/或PBMC中检测到瞬时RFHV DNA。将猪尾供体的全唾液中的同源RFHVMn接种到一只幼年猕猴的颊囊中。这只动物变得免疫抑制，发展为猿艾滋病，并在接种后23周被安乐死。唾液和PBMC中RFHV DNA水平在17周后仍低于检测水平，表明在AIDS的快速发展过程中没有RFHVMn感染的重新激活。另一只幼年猕猴用来自食蟹猴供体唾液的纯化病毒体的静脉内接种的异源RFHVMf感染。幼年受者保持免疫活性，发展高水平的持久性抗RFHV和SIV抗体。在唾液和PBMC中最初存在的RFHVMf DNA到第19周降低到不可检测的水平后，通过额外接种、用纯化的SRV- 2或SIV进行实验性感染或用环孢菌素或地塞米松进行免疫抑制治疗来重新激活感染的所有尝试都不成功。在该受体中还检测到异源LCV传播，其特征在于唾液（> 10（6）基因组/ml）和PBMC（> 10（4）基因组/百万个细胞）中持续高水平的来自食蟹猴供体的LCVMf DNA，以及高水平的抗LCV抗体。在初次接种后209周处死猕猴。在唾液腺、扁桃体和其他淋巴器官中检测到低水平的LCVMf DNA，而RFHVMf DNA低于检测水平。这些结果表明RFHV和LCV从唾液中成功共传播，并证明了不同γ疱疹病毒谱系的差异裂解活化，这是由于推测的生物学和嗜性差异以及宿主免疫系统的控制。虽然这个最初的试点传播研究只利用了两只猕猴，它提供了第一个证据的实验传播的猕猴同源KSHV，设置阶段更大的传播研究，以检查差异激活的Rhadinovirus和Lymphocyptovirus感染和免疫抑制的病理影响。
Macaque RFHV and LCV are close homologs of human KSHV and EBV, respectively. No experimental model of RFHV has been developed due to the lack of a source of culturable infectious virus. Screening of macaques at the Washington National Primate Research Center detected RFHV in saliva of SIV-infected macaques from previous vaccine studies. A pilot experimental infection of two naive juvenile pig-tailed macaques was initiated by inoculation of saliva from SIV-infected pig-tailed and cynomolgus macaque donors, which contained high levels of DNA (> 10(6) genomes/ml) of the respective species-specific RFHV strain. Both juvenile recipients developed SIV and RFHV infections with RFHV DNA detected transiently in saliva and/or PBMC around week 16 post-infection. One juvenile macaque was infected with the homologous RFHVMn from whole saliva of a pig-tailed donor, which had been inoculated into the cheek pouch. This animal became immunosuppressed, developing simian AIDS and was euthanized 23 weeks after inoculation. The levels of RFHV DNA in saliva and PBMC remained below the level of detection after week 17, showing no reactivation of the RFHVMn infection during the rapid development of AIDS. The other juvenile macaque was infected with the heterologous RFHVMf from i.v. inoculation of purified virions from saliva of a cynomolgus donor. The juvenile recipient remained immunocompetent, developing high levels of persistent anti-RFHV and -SIV antibodies. After the initial presence of RFHVMf DNA in saliva and PBMC decreased to undetectable levels by week 19, all attempts to reactivate the infection through additional inoculations, experimental infection with purified SRV- 2 or SIV, or immunosuppressive treatments with cyclosporine or dexamethasone were unsuccessful. An heterologous LCV transmission was also detected in this recipient, characterized by continual high levels of LCVMf DNA from the cynomolgus donor in both saliva (> 10(6) genomes/ml) and PBMC (> 10(4) genomes/million cells), coupled with high levels of anti-LCV antibodies. The macaque was sacrificed 209 weeks after the initial inoculation. Low levels of LCVMf DNA were detected in salivary glands, tonsils and other lymphoid organs, while RFHVMf DNA was below the level of detection. These results show successful co-transmission of RFHV and LCV from saliva and demonstrate differential lytic activation of the different gammaherpesvirus lineages due to presumed differences in biology and tropism and control by the host immune system. Although this initial pilot transmission study utilized only two macaques, it provides the first evidence for experimental transmission of the macaque homolog of KSHV, setting the stage for larger transmission studies to examine the differential activation of rhadinovirus and lymphocryptovirus infections and the pathological effects of immunosuppression.